Excessive accumulation of smooth muscle in the airway (smooth muscle remodeling), may contribute to airway obstruction and disease progression in asthma, and recent studies have identified factors that could contribute to this process. At the same time, basic immunological research suggests that asthma is fundamentally a T helper type 2 (Th2)-driven inflammatory disease. However, whether Th2 inflammation is the major factor underlying airway remodeling in human asthma is uncertain. Our preliminary data demonstrate that the canonical mediator of Th2 inflammation in the airway, interleukin-13 (IL-13), drives inflammation in only a subset of patients with asthma. This subset with IL-13-driven asthma comprises half of our asthmatics and represents a distinct clinical and pathological phenotype. With regard to smooth muscle, our preliminary data indicate that remodeling is markedly increased in IL-13 driven asthma, suggesting that Th2 inflammation contributes directly to smooth muscle remodeling in human asthma. Our data also identify a matricellular protein, periostin, as a mediator which may link IL-13 driven inflammation to airway remodeling in asthma. On the other hand, our data suggest that some degree of smooth muscle remodeling may be present in non-IL-13 driven asthma as well, implying additional non-Th2-driven pathways in some patients. If so, this implies that ASM remodeling is a fundamental abnormality common to all phenotypes of asthma. On the basis of these data, we propose three aims to address the following hypotheses: 1) that IL-13-driven inflammation enhances ASM remodeling, 2) that periostin, secreted by resident lung cells in response to IL-13, mediates ASM remodeling in IL-13 driven asthma, and 3) that additional non-IL-13 driven pathways contribute to ASM remodeling in some patients and that these pathways can be identified using translational and genomic approaches. These studies will be performed in vivo by applying bronchoscopy, design-based stereology, laser capture microdissection and genomics in a detailed study of asthmatics and healthy controls and in vitro using cell culture models. These studies will leverage innovative methodologies for the study of ASM in humans and address the interplay between inflammation, remodeling and ASM synthetic function. Importantly, our results will address a critical barrier to progress in the field, whatever the result. If ASM remodeling is enhanced in IL- 13 driven asthma, then strategies that target Th2 inflammation or specific downstream mediators such as periostin, should improve ASM remodeling. However, if ASM remodeling can also occur in non-IL-13-driven asthma, then our studies will guide further research in the field by directing attention to non-Th2 pathways of ASM dysfunction in asthma which may be novel and are not targeted by current therapies. (End of Abstract)